Although Alzheimer's disease is typified by global and progressive cognitive decline, the emergence of clinically-significant behavioral syndromes is also common in this disorder (Wragg and Jeste, 1989). Estimates of the prevalence of major depression among patients with Alzheimer's disease has ranged from 0% to 86%, with most estimates in the range of 20% to 25%. Yet, the neuropathological and neurochemical correlates of this important source of comorbidity have not been systematically studied. Previous clinical, pharmacologic, and biochemical evidence have supported a role for several neurotransmitter systems in the pathogenesis of major depression. In the current application, we propose to examine the morphological correlates of major depression in the context of Alzheimer's disease by focusing on three aminergic nuclei, the locus ceruleus, the substantia nigra, and the dorsal raphe nuclei, as well as the respective neurotransmitter/metabolite levels in the projection areas of these nuclei. As an index of cholinergic dysfunction, the relationship of choline acetyltransferase-specific activity to the emergence of major depression will also be determined. Hypotheses: Major depression in the context of AD is associated with (1) increased cytopathologic features in the locus ceruleus, substantia nigra, and the dorsal raphe nucleus; (2) a reduction in the respective monoaminergic neurotransmitters norepinephrine, dopamine, and serotonin in the projection areas of these nuclei; and (3) the relative preservation of ChAT activity in the brain regions to which these nuclei project. As an ancillary specific aim, we will also test the hypothesis that a family history of major depressive disorder among first-degree relatives is a risk factor for the emergence of major depression in probands with AD.